Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, FL, USA.
Hum Mol Genet. 2012 May 15;21(10):2288-97. doi: 10.1093/hmg/dds049. Epub 2012 Feb 21.
Aging is an intricate process that increases susceptibility to sarcopenia and cardiovascular diseases. The accumulation of mitochondrial DNA (mtDNA) mutations is believed to contribute to mitochondrial dysfunction, potentially shortening lifespan. The mtDNA mutator mouse, a mouse model with a proofreading-deficient mtDNA polymerase γ, was shown to develop a premature aging phenotype, including sarcopenia, cardiomyopathy and decreased lifespan. This phenotype was associated with an accumulation of mtDNA mutations and mitochondrial dysfunction. We found that increased expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a crucial regulator of mitochondrial biogenesis and function, in the muscle of mutator mice increased mitochondrial biogenesis and function and also improved the skeletal muscle and heart phenotypes of the mice. Deep sequencing analysis of their mtDNA showed that the increased mitochondrial biogenesis did not reduce the accumulation of mtDNA mutations but rather caused a small increase. These results indicate that increased muscle PGC-1α expression is able to improve some premature aging phenotypes in the mutator mice without reverting the accumulation of mtDNA mutations.
衰老是一个复杂的过程，会增加患上肌肉减少症和心血管疾病的易感性。线粒体 DNA（mtDNA）突变的积累被认为导致线粒体功能障碍，可能会缩短寿命。具有校正缺陷的 mtDNA 聚合酶 γ 的 mtDNA 突变体小鼠是一种小鼠模型，表现出过早衰老的表型，包括肌肉减少症、心肌病和寿命缩短。这种表型与 mtDNA 突变的积累和线粒体功能障碍有关。我们发现，突变体小鼠肌肉中过氧化物酶体增殖物激活受体 γ 共激活因子 1α（PGC-1α）的表达增加，这是线粒体生物发生和功能的关键调节因子，增加了线粒体生物发生和功能，也改善了小鼠的骨骼肌和心脏表型。对其 mtDNA 的深度测序分析表明，增加的线粒体生物发生并没有减少 mtDNA 突变的积累，而是导致了微小的增加。这些结果表明，增加肌肉 PGC-1α 的表达能够改善突变体小鼠的一些过早衰老表型，而不会逆转 mtDNA 突变的积累。
